INTRAVENOUS GENE THERAPY FOR FAMILIAL HYPERCHOLESTEROLEMIA USING LIGAND-FACILITATED TRANSFER OF A LIPOSOME : LDL RECEPTOR GENE COMPLEX

使用配体促进脂质体转移的静脉内基因治疗家族性高胆固醇血症：LDL 受体基因复合物

• 批准号: 13671178
• 负责人: TANAKA Akira
• 金额: $ 2.56万
• 依托单位: KANTO-GAKUIN UNIVERSITY (2002)Tokyo Medical and Dental University (2001)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671178/
• 关键词: GENE THERAPY; WHHL RABBIT; LDL RECEPTOR; RIPOSOME; TRANSFERRIN; LDL RECEPTOR GENE; FAMILIAL HYPERCHOLESTEROLEMIA; TRANSFER OF GENE; WHHL家兎; トランスフェリン受容体; リポリーム; LDLコレステロール

Familial hypercholesterolemia (FH) is an autosomal dominant disorder because of a mutation in the low-density lipoprotein receptor (LDLR) gene. Although lowering plasma cholesterol decreases the risk of coronary artery disease, FH patients respond poorly to pharmacologic treatment. Transferrin-facilitated intravenous transfer of a cationic liposome rabbit LDLR cDNA complex alleviated hypercholesterolemia in Watanabe Heritable rabbits (WHHL), an animal model of FH. Intravenous treatment does dependently decreased plasma total and LDL cholesterol levels, correlating with an increased level of LDLR mRNA transcripts in leukocytes. Transferrin-facilitated intravenous delivery of cationic liposome LDLR gene complexes could serve as an important adjunct therapy for the treatment of FH.

家族性高胆固醇血症（FH）是一种常染色体显性遗传疾病，由于低密度脂蛋白受体（LDLR）基因突变。虽然降低血浆胆固醇可降低冠状动脉疾病的风险，但FH患者对药物治疗的反应较差。转铁蛋白促进阳离子脂质体兔LDLR cDNA复合物的静脉内转移减轻了Watanabe遗传兔（WHHL）的高胆固醇血症，这是FH的动物模型。静脉给药确实依赖性地降低血浆总胆固醇和LDL胆固醇水平，与白细胞中LDLR mRNA转录水平升高相关。转铁蛋白介导的阳离子脂质体LDLR基因复合物静脉给药可作为治疗FH的重要辅助治疗手段。

项目成果

Shitiri M, Tanaka A, et al.: "Intravenous gene therapy for familial hypercholesterolemia using ligand-facilitated transfer of a liposome : LDL receptor gene complex"Gene Therapy. (in press).

Shitiri M、Tanaka A 等人：“利用脂质体的配体促进转移进行家族性高胆固醇血症的静脉基因治疗：LDL 受体基因复合物”基因治疗。

Nawa T, Tanaka A, et al.: "Expression of transcriptional repressor ATF3/LRF1 in human atherosclerosis : Colocalization and possible involvement in cell death of vascular endothelial cells cells"Atherosclerosis. 161. 281-291 (2002)

Nawa T、Tanaka A 等人：“人类动脉粥样硬化中转录抑制因子 ATF3/LRF1 的表达：共定位并可能参与血管内皮细胞的细胞死亡”动脉粥样硬化。

Nawa T, Tanaka A, et a.: "Expression of transcriptional repressor ATF3/LRF1 in human atherosclerosis : Colocalization and possible involvement in cell death of vascular endothelial cells"Atherosclerosis. 161. 281-291 (2002)

Nawa T、Tanaka A 等人：“转录抑制因子 ATF3/LRF1 在人类动脉粥样硬化中的表达：共定位并可能参与血管内皮细胞的细胞死亡”动脉粥样硬化。

Doi M, Shichiri M, et al.: "Cytokine-activated Jak-2 is involved in inducible nitric oxide synthase expression independent from NF-kB activation in vascular smooth muscle cells"Atherosclerosis. 160. 123-132 (2002)

Doi M、Shichiri M 等人：“细胞因子激活的 Jak-2 参与诱导型一氧化氮合酶表达，不依赖于血管平滑肌细胞中 NF-kB 的激活”动脉粥样硬化。

Ai M, Tanaka A, et al.: "relationship between insulin concentration and plasma remnant lipoprotein response to an oral fat load in patients with type 2 diabetes"J Am Coll Cardiol. 38. 1623-1632 (2001)

Ai M、Tanaka A 等人：“2 型糖尿病患者胰岛素浓度和血浆残余脂蛋白对口腔脂肪负荷反应之间的关系”J Am Coll Cardiol。